| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients diagnosed with ventilator-associated pneumonia |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is to:
• Compare the clinical response rate of IV doripenem vs. IV imipenem at the test-of-cure (TOC) visit in microbiologically evaluable patients with ventilator-associated pneumonia (VAP). The TOC visit will be conducted 7 to 14 days after completion of IV study therapy.
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| E.2.2 | Secondary objectives of the trial |
• Compare the clinical response rate of IV doripenem vs. IV imipenem in clinically evaluable patients at the end of IV therapy, TOC and late follow-up.
• Compare the per patient microbiological response rate of IV doripenem vs. IV imipenem at the end of IV therapy, TOC and LFU.
• Compare the per pathogen microbiological response rate in IV doripenem group vs. IV imipenem group at the end of IV and the TOC.
• Compare the time to decrease in baseline CPIS by at least 2 points in IV doripenem group vs. IV imipenem group.
• Compare the number of days of study drug therapy in IV doripenem group vs. IV imipenem group, overall and in late-onset VAP.
• Compare the mortality rate at 28 days post start of therapy in IV doripenem group vs. IV imipenem group.
• Compare the safety profile of IV doripenem with that of IV imipenem |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for participation in this study.
1. Males or females > 18 years old being treated in an ICU.
2. Patient hospitalized for ≥ 48 hours or has prior hospital admission of at least 48 hours and was discharged within the last 7 days. Non-ambulatory residents of chronic care facilities admitted with pneumonia are also eligible.
3. Patient has received mechanical ventilation for > 24 hours or has weaned from mechanical ventilation within 72 hours.
4. CPIS > 5.
5. Presence of a new or progressive infiltrate on chest x-ray.
6. At least 1 of the following:
a. Fever, defined as an oral temperature > 38˚ C (100.4˚ F) or a rectal/core temperature > 39˚ C (102.2˚ F) or hypothermia, defined as a rectal/core body temperature of < 35˚ C (95.2˚ F)
b. Elevated total peripheral WBC count (≥ 10,000/mm3) or > 15% immature forms (bands) regardless of total peripheral WBC count; or leukopenia with total peripheral WBC < 4,500/mm3 (caused by the infection)
7. Infection is known or presumed at time of enrollment to be caused by microorganisms susceptible to both study drugs. The addition of vancomycin is allowed for suspected or confirmed MRSA or Enterococcus infection. Patients can be enrolled before culture results are known.
8. Females of childbearing potential must have a negative serum pregnancy test (ß human chorionic gonadotropin [ß-hCG]) prior to enrollment in the study and, subsequently, for at least 1 month after study treatment must agree to use adequate birth control measures. Hormonal contraceptives are not to be used as the sole method of birth control.
9. Patient requires IV antibacterial therapy.
10. Patient is able to provide informed consent. If the patient is unable, the patient’s legally acceptable representative may provide written consent as approved by institutional specific guidelines.
11. Microbiologic Inclusion Criteria: All patients who meet the clinical and radiographic criteria for VAP, must have an acceptable specimen of respiratory tract secretions taken prior to inclusion and randomization into this study. However, patients can be enrolled in this study before the results of the culture are known. The specimen should be obtained by endotracheal aspiration or bronchoscopy, if scheduled for clinical reasons, either by BAL or protected-specimen brush. Specimens obtained within 24 hours prior to enrollment are acceptable if no antibiotic therapy is given since the time that specimen was obtained.
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| E.4 | Principal exclusion criteria |
Patients must NOT meet any of the following exclusion criteria:
1. Known at study entry to have VAP caused by pathogen(s) resistant to either imipenem or meropenem (other than MRSA or Enterococcus, which can be treated with vancomycin).
2. APACHE II score <8 or >25.
3. Considered unlikely to survive to the LFU visit, 28 -35 days after completion of study therapy.
4. Patients with an order of no cardiopulmonary resuscitation in case of cardiac arrest.
5. Presence of a concomitant extrapulmonary infection that requires non-study systemic antibacterial therapy or prolonged (> 14 days) antimicrobial treatment.
6. Presence of structural lung disease, emphysema, or ARDS (eg diffuse radiographic infiltrates and Pa02 to FiO2 ratio < 200).
7. Presence of cavitary lung disease based on chest x-ray findings, primary lung cancer or another malignancy metastatic to the lungs, cystic fibrosis, or known or suspected Pneumocystis carinii pneumonia.
8. Any rapidly progressing disease or immediately life-threatening illness, including acute hepatic failure or septic shock.
9. Use of systemic antibiotic therapy (with activity against the likely causative respiratory pathogens) for ≥ 24 hours within 72 hours prior to randomization unless the patient is a clinical failure for VAP or has a new infiltrate that developed while the patient was taking the prior antibiotic regimen.
10. The need for concomitant systemic antimicrobial agents (other than vancomycin or amikacin) or Xigris® (drotregogin alpha) in addition to study drug(s).
11. End stage renal impairment requiring peritoneal dialysis, hemodialysis or hemofiltration.
12. The presence of hepatic disease:
i. ALT or AST > 4 x ULN; values up to 6 x ULN are allowed if acute and, if in the opinion of the investigator, directly related to the infectious process being treated.
ii. Bilirubin > 2 x ULN, unless isolated hyperbilirubinemia is directly related to the acute process.
iii. Alkaline phosphatase > 4 x ULN. Patients with values up to 5 x ULN are eligible if this value is historically stable.
13. Hematocrit < 20%.
14. Neutropenia with absolute neutrophil count < 500 cells/mm3.
15. Platelet count < 40,000/mm3.
16. Coagulation tests > 1.5 x ULN (PT, PTT, or INR). Patients on anticoagulants with values > 1.5 x ULN can be enrolled, provided these values are stable and within the therapeutic range.
17. Immunocompromising illness including known infection with human immunodeficiency virus (HIV), AIDS, hematological malignancy, and bone marrow transplantation, or immunosuppressive therapy including cancer chemotherapy, medications for prevention of organ transplantation rejection, and the administration of corticosteroids equivalent to or greater than 10 mg of prednisone per day administered for more than 14 days.
18. Women who are pregnant, nursing, or if of child bearing potential not using a medically accepted, effective method of birth control (e.g., condom, oral contraceptive, indwelling intrauterine device, or sexual abstinence).
19. History of moderate or severe hypersensitivity reactions to carbapenems, penicillins, other beta-lactam antibiotics, or ß-lactamase inhibitors.
20. Participation in any investigational drug or device study within 30 days prior to study entry.
21. Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the patient or the quality of study data.
22. Patients who previously received more than 1 dose of a carbapenem for the current infection.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Clinical response rate at the TOC visit in the microbiologically evaluable population. The TOC visit will be conducted 7-14 days after the completion of IV study drug therapy. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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